US9315451B2ActiveUtilityPatentIndex 78
Tetracycline compounds
Est. expiryMay 8, 2029(~2.8 yrs left)· nominal 20-yr term from priority
Inventors:CHEN CHI-LICLARK ROGER BDENG YONGHONGHE MINSHENGPLAMONDON LOUISSUN CUIXIANGXIAO XIAO-YIRÖNN Magnus
C07D 209/14C07C 237/26C07D 211/14C07D 223/04C07C 2603/74A61P 31/04C07C 231/10C07D 401/04C07D 295/155C07D 209/04C07D 221/20C07C 311/06C07D 207/09C07D 295/108C07D 295/15C07D 413/06C07C 67/317C07D 209/52C07D 209/44C07C 2601/04C07C 2601/14C07D 471/10C07C 2602/08C07D 213/74C07D 207/10C07D 207/16C07D 241/04C07D 307/22C07D 205/04C07D 261/20C07D 223/32C07D 207/06C07C 67/31C07D 211/46C07C 2601/08C07D 207/14C07D 295/13C07D 295/135C07C 2603/46C07C 2601/02C07C 275/24C07C 2602/50C07C 2602/42C07C 2601/18C07D 207/08C07C 67/08C07D 223/14C07D 211/18C07D 295/185C07D 211/34C07C 67/313C07D 211/62C07C 2602/24C07D 211/58C07D 295/26C07D 487/10A61P 31/12C07C 311/19C07C 67/307C07C 51/353C07C 2101/04C07C 2102/08C07C 2102/42C07C 2101/08C07C 2101/14C07C 2101/02C07C 2103/74
78
PatentIndex Score
10
Cited by
120
References
15
Claims
Abstract
The present invention is directed to a compound represented by Structural Formula (I): or a pharmaceutically acceptable salt thereof. The variables for Structural Formula I are defined herein. Also described is a pharmaceutical composition comprising the compound of Structural Formula I and its therapeutic use.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1. A compound of Formula (II):
or a pharmaceutically acceptable salt thereof, wherein:
X is selected from bromo, fluoro, chloro, C 1 -C 6 fluoroalkyl, —O—C 1 -C 6 alkyl, —S(O) m —C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, —O—C 3 -C 7 cycloalkyl, —S(O) m —C 3 -C 7 cycloalkyl, —CN, and —NH—C(O)—(C 1 -C 6 alkylene)-N(R 4 )(R 5 ), wherein each alkyl, alkylene or cycloalkyl in the group represented by X is optionally substituted with fluoro;
R 1a is selected from hydrogen, C 1 -C 4 alkyl, and C 3 -C 10 carbocyclyl;
R 2 is selected from hydrogen, C 1 -C 12 alkyl, —C 0 -C 6 alkylene-C 3 -C 10 carbocyclyl, and —C 0 -C 6 alkylene-(4-13 membered) heterocyclyl;
R 3 is selected from hydrogen, C 1 -C 8 alkyl, —C 0 -C 6 alkylene-C 3 -C 10 carbocyclyl, —C 0 -C 6 alkylene-(4-13 membered) heterocyclyl, —C(O)—C 1 -C 6 alkyl, —C 0 -C 6 alkylene—C(O)N(R 4 )(R 5 ), —C(O)—C 1 -C 6 alkylene-N(R 4 )(R 5 ), —C 2 -C 6 alkylene—N(R 4 )(R 5 ), —S(O) m —C 1 -C 6 alkyl, —S(O) m —C 3 -C 10 carbocyclyl, and —S(O) m -(4-13 membered) heterocyclyl, wherein each alkyl, carbocyclyl, alkylene or heterocyclyl in the group represented by R 2 or R 3 is optionally and independently substituted with one or more substituents independently selected from fluoro, chloro, —OH, —O—C 1 -C 4 alkyl, C 1 -C 4 alkyl, fluoro-substituted-C 1 -C 4 alkyl, —N(R 4 )(R 5 ), C 3 -C 10 carbocyclyl or a (4-13 membered) heterocyclyl; or
R 2 and R 3 taken together with the nitrogen atom to which they are bound form a (4-7 membered) monocyclic heterocylic ring, or a (6-13 membered) bicyclic, spirocyclic or bridged heterocylic ring, wherein the (4-7 membered) monocyclic heterocylic ring, or the (6-13 membered) bicyclic, spirocyclic or bridged heterocyclic ring optionally comprises 1 to 4 additional heteroatoms independently selected from N, S and O; and wherein the (4-7 membered) monocyclic heterocylic ring, or the (6-13 membered) bicyclic, spirocyclic or bridged heterocyclic ring is optionally substituted with one or more substituents independently selected from C 3 -C 10 carbocyclyl, (4-13membered) heterocyclyl, fluoro, chloro, —OH, —C 1 -C 4 fluoroalkyl, —C 1 -C 4 alkyl, —O—C 3 -C 10 carbocyclyl, —O—(4-13 membered) heterocyclyl, —C 0 -C 4 alkylene-O—C 1 -C 4 alkyl, —C 0 -C 4 alkylene-O—C 1 -C 4 fluoroalkyl, ═O, —C(O)—C 1 -C 4 alkyl, —C(O)N(R 4 )(R 5 ), —N(R 4 )—C(O)—C 1 -C 4 alkyl, and —C 0 -C 4 alkylene-N(R 4 )(R 5 ), and wherein each carbocyclyl or heterocyclyl substituent is optionally substituted with fluoro, chloro, —OH, C 1 -C 4 fluoroalkyl, C 1 -C 4 alkyl, —O—C 1 -C 4 alkyl, —O—C 1 -C 4 fluoroalkyl, —NH 2 , —NH(C 1 -C 4 alkyl), or —N(C 1 -C 4 alkyl) 2 ;
each of R 4 and R 5 is independently selected from hydrogen and C 1 -C 4 alkyl; or
R 4 and R 5 taken together with the nitrogen atom to which they are bound form a (4-7 membered) heterocylic ring optionally comprising one additional heteroatom selected from N, S and O, wherein the (4-7 membered) heterocylic ring is optionally substituted with fluoro, chloro, —OH, fluoro-substituted C 1 -C 4 alkyl, —C 1 -C 4 alkyl, or —C 1 -C 4 alkylene-O—C 1 -C 4 alkyl, and is optionally fused to phenyl;
each m is independently 0, 1 or 2.
2. The compound of claim 1 , wherein:
R 1a is selected from hydrogen and methyl;
R 2 is selected from hydrogen, C 1 -C 3 straight chained alkyl, C 1 -C 3 straight chained fluoroalkyl, cyclopropyl, and —CH 2 -cyclopropyl;
R 3 is selected from hydrogen, C 1 -C 8 alkyl, —CH 2 —CHF 2 , —C 2 -C 6 alkylene-O—C 1 -C 3 alkyl, —C 3 -C 10 cycloalkyl, —C 3 -C 10 cycloalkyl-substituted C 1 -C 3 alkyl, cyclopropyl-substituted cyclopropyl, —(CH 2 ) 2 -phenyl, and —S(O) 2 -phenyl, when R 2 is hydrogen or C 1 -C 2 alkyl, R 3 is additionally selected from benzyl; or
R 2 and R 3 taken together with the nitrogen atom to which they are bound form a ring selected from pyrrolidine, piperidine, piperazine or morpholine, wherein the ring is optionally substituted with one or more substituents independently selected from —OH, —C 1 -C 3 alkyl and —C 1 -C 3 alkylene-O—C 1 -C 3 alkyl, and wherein the ring is optionally fused to phenyl or spirofused to cyclopropyl.
3. The compound of claim 1 , wherein:
R 1a is selected from hydrogen and methyl;
R 2 is selected from hydrogen, C 1 -C 3 straight chained alkyl and —CH 2 -cyclopropyl;
R 3 is selected from hydrogen, C 1 -C 8 alkyl, —CH 2 —CHF 2 , —C 1 -C 6 alkylene-O—C 1 -C 3 alkyl, C 3 -C 10 cycloalkyl, —(CH 2 ) 2 -phenyl and C 3 -C 10 cycloalkyl-substituted C 1 -C 3 alkyl, wherein each cycloalkyl in the group represented by R 3 is optionally substituted with —C 1 -C 3 alkyl or optionally benzofused and when R 2 is hydrogen or —C 1 -C 2 alkyl, R 3 is additionally selected from benzyl; or
R 2 and R 3 taken together with the nitrogen atom to which they are bound form a ring selected from pyrrolidine and piperidine, wherein the ring is optionally substituted with one or more substituents independently selected from fluoro —C 1 -C 3 alkyl and —C 1 -C 3 alkylene-O—C 1 -C 3 alkyl, and wherein the ring is optionally fused to phenyl or spirofused to cyclopropyl.
4. The compound of claim 1 , wherein X is fluoro or chloro.
5. The compound of claim 4 , wherein:
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is chloro and —CH(R 1a )—NR 2 R 3 is
X is chloro and —CH(R 1a )—NR 2 R 3 is
X is chloro and —CH(R 1a )—NR 2 R 3 is
X is chloro and —CH(R 1a )—NR 2 R 3 is
X is chloro and —CH(R 1a )—NR 2 R 3 is
X is chloro and —CH(R 1a )—NR 2 R 3 is
X is chloro and —CH(R 1a )—NR 2 R 3 is
X is chloro and —CH(R 1a )—NR 2 R 3 is
X is chloro and —CH(R 1a )—NR 2 R 3 is
X is chloro and —CH(R 1a )—NR 2 R 3 is
6. The compound of claim 1 , wherein X is —OCH 3 , —CF 3 , Cl, or F.
7. The compound of claim 1 , wherein X is selected from fluoro, chloro, and —CN.
8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound of claim 1 .
9. A method for reducing a bacterial infection in a subject comprising administering to the subject an effective amount of the compound of claim 1 .
10. The method of claim 9 , wherein the bacterial infection is caused by a Gram-positive organism.
11. The method of claim 9 , wherein the bacterial infection is caused by a Gram-negative organism.
12. The method of claim 9 , wherein the bacterial infection is caused by an organism selected from the group consisting of rickettsiae, chlamydiae, and Mycoplasma pneumoniae.
13. The method of claim 9 , wherein the bacterial infection is caused by an organism resistant to tetracycline.
14. The method of claim 9 , wherein the bacterial infection is caused by an organism resistant to methicillin.
15. The method of claim 9 , wherein the bacterial infection is caused by an organism resistant to vancomycin.Cited by (0)
No later patents cite this yet.
References (0)
No backward citations on record.